Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
The present invention relates to asthma therapy. Bronchial asthma in mammals is characterized by inflammation of the airways, exaggerated airway reactivity to bronchoconstrictor agonists, and attenuated beta-adrenoceptor-mediated airway relaxation (Bai, 1990 Am. Rev. Respir. Dis. 141:552-557; Goldie et al., 1986, Br. J. Clin. Pharmacol. 22:669-676; McFadden et al., 1994, Am. J. Respir. Crit. Care Med. 150:523-526). In humans with atopic asthma, mast cell activation has been implicated in mediating the immediate bronchoconstrictor response which acutely follows antigen inhalation. This response is a process which involves IgE-mediated activation of the high affinity IgE receptor (FcεRI), leading to cellular degranulation and the release of various mast cell-derived mediators including histamine, eicosanoids, and specific cytokines (Metzger, 1992, Immunol. Rev. 125:37-48; Beaven et al., 1993, Immunol. Today 14:222-226; Galli, 1993, N. Engl. J. Meda 328:257-265).
The identification of Fc receptors on other cell types in the lung (e.g., mononuclear cells, eosinophils, and dendritic cells) suggests that, apart from mast cells per se, these other cell types may also serve to propagate the pro-inflammatory allergic pulmonary response, most likely via the orchestrated extended release of various cytokines (Walker et al., 1992, Am. Rev. Respir. Dis. 146:109-115; Watson et al., 1993, Am. J. Respir. Cell Mol. Biol. 8:365-369; Capron et al., 1984, J. Immunol. 132:462-468; Beasley et al., 1989, Am. Rev. Respir. Dis. 139:806-817; Litchfield et al., 1992, J. Asthma 29:181-191; Barnes et al., 1988, Pharmacol. Rev. 40:49-84; Borish et al., 1991, J. Immunol. 146:63-67). It is believed that immune complex/Fc receptor interactions expressed by these cells, i.e., mononuclear cells, eosinophils, and dendritic cells, potentially underlie the progression of the airway inflammatory and bronchoconstrictor responses in asthma, wherein the immediate bronchoconstriction accompanying antigen exposure is followed by the development of the late phase asthmatic response involving various proinflammatory cells. Indeed, recent studies have demonstrated that expression of the inducible form of the low affinity IgE receptor (FcεRII or CD23) is upregulated on monocytes and alveolar macrophages (Williams et al., 1992, J. Immunol. 149:2823-2829), as well as on circulating B lymphocytes (Gagro et al., 1993, Int. Arch. Allergy Immunol. 101:203-208; Rabatic et al., 1993, Exp. Immunol. 94:337-340) isolated from atopic asthmatic subjects. Similarly, exposure of asthmatic subjects to allergen and treatment of isolated monocytes with specific cytokines have been shown to up-regulate FcεRII expression on mononuclear phagocytes (Williams et al., 1992, J. Immunol. 149:2823-2829; Joseph et al., 1983, J. Clin. Invest. 71:221-230). These findings suggest that altered Fc receptor expression and action in some cell types may contribute to the overall pro-inflammatory asthmatic response. While it is known that exposure of isolated rabbit and human airway smooth muscle (ASM) to atopic asthmatic serum induces the autocrine release and action of specific cytokines (notably Interleukins) by the sensitized ASM cells (Hakonarson et al., 1997, J. Clin. Invest. 99:117-124), the mechanism by which this sensitization is mediated has not been disclosed.
Current treatment options for asthma include medications that control the airway inflammatory component of the disease, (e.g., primarily corticosteroids, sodium cromolyn, methylxanthines, leukotriene modifiers), systemic administration of an anti-IgE antibody (e.g., Xolair), and rapid relief medications that counteract bronchospasm, (e.g., primarily beta-adrenergic agents). There are several disadvantages to using these medications as follows. There is a potential lack of effective sustained action; there are side effects associated with prolonged use of these medications, particularly in the case of corticosteroids and beta-adrenergic agents; there is a progressive loss of sensitivity to these treatments after prolonged use; there is limited efficacy of any of these agents in severe cases of asthma; these agents are non-selective, i.e., they do not specifically target the lung, therefore, side-effects affecting other organs are a potential risk. Furthermore, there are data which document an increased risk of dying from bronchial asthma following prolonged treatment of asthma using long-acting beta-adrenergic agents such as fenoterol (Pearce et al., 1990, Thorax 45:170-175; Spitzer et al., 1992, N. Engl. J. Med. 326:560-561).
Approximately fifteen million individuals in the U.S. have asthma and the disease is the cause of more than five thousand deaths annually in the U.S. In children, asthma represents the most prevalent chronic disease, requiring the most frequent use of emergency room visits and hospitalizations. The overall annual cost for asthma care in the U.S. is estimated to be in the range of billions of dollars. Although the disease represents a complex genetic disorder wherein multiple genes interact with each other and with the environment to trigger variable expression of the asthma phenotype, it is well established that IgE plays a central role in mediating the pulmonary inflammatory response and associated altered airway reactivity seen in allergic asthmatic individuals.
It has previously been shown that (1) airway smooth muscle (ASM) cells express CD23, the low affinity receptor for IgE, (2) CD23 expression is increased in ASM tissues isolated from allergic asthmatic individuals, and (3) activation of CD23 in ASM tissues by exposure to either high IgE-containing serum from atopic asthmatic individuals or IgE immune complexes elicits pro-asthmatic changes in ASM constrictor and relaxation responsiveness that characterize allergic asthma.
Accordingly, there exists a need for other safe and effective novel compositions and methods for treatment of asthma. The present invention satisfies this need and provides related advantages that overcome some of the deficiencies of the prior art.